N-protected/N-substituted-beta-amino hydroxy sulfonates

ABSTRACT

N-protected/N-substituted alpha-amino aldehydes, which are useful as pharmaceuticals and pharmaceutical intermediates, can be stored and shipped in a more stable form as N-protected/N-substituted-beta-amino hydroxy sulfonates which can be readily converted back into the aldehyde under mild conditions. The present invention relates to N-protected/N-substituted-beta-amino hydroxy sulfonates and their preparation and use.

This application is a divisional of Ser. No. 08/747,825 filed Nov. 13,1996 now U.S. Pat. No. 5,847,201 also claims priority benefits from U.S.provisional application Ser. No. 60/006,860 filed Nov. 16, 1995.

BACKGROUND OF THE INVENTION

Synthesis of many pharmaceuticals, such as aspartyl protease inhibitors,involve the preparation of beta-amino alcohol intermediates fromN-protected/N-substituted alpha-amino aldehydes in one or more steps. Inparticular, pharmaceuticals containing at least one chiral center can beprepared from chiral N-protected/N-substituted alpha-amino aldehydes.Examples of the preparation of chiral N-protected/N-substitutedalpha-amino aldehydes and their use as pharmaceutical intermediates inthe preparation of aspartyl protease inhibitors, such as renin and HIVprotease inhibitors, dietetic sweeteners, bestatin derivatives can befound in Chem. Pharm. Bull. 30:1921-1924, 1982; J. Org. Chem.43:2480-2482, 1978; J. Org. Chem. 47:3016-3018, 1982; Tet. Let.27:2337-2340, 1986; PCT/US94/12201; WO 93/23388; WO 94/04491; WO94/04492; WO 94/04493; U.S. Pat. No. 4,990,669; Tet. Let. 30:5421-5424,1989; Philos. Trans. R. Soc. London, A, 326:573-578, 1988; Chem. Rev.89:149-164, 1989; and J. Org. Chem. 52:2361-2364, 1987. In addition,N-substituted alpha-amino aldehydes are known to have cysteineproteinase inhibition activity, such as papin, calpain and cathepsininhibition (see for example EP 393457).

A drawback to the use of N-protected/N-substituted alpha-amino aldehydesis their instability to storage, particularly long term storage, (seeU.S. Pat. No. 4,990,669; Chem. Rev. 89:149-164, 1989; J. Org. Chem.47:3016-3018, 1982; and J. Am. Chem. Soc. 109:236-239, 1987). This isparticularly true for use of N-protected/N-substituted alpha-aminoaldehydes in manufacturing processes, where it is sometimes advantageousto store and ship large quantities of intermediates, such as theN-protected/N-substituted alpha-amino aldehydes, to other locations forprocessing. Generally, N-protected/N-substituted alpha-amino aldehydesare used promptly following preparation and are not shipped or storedfor long periods. Some efforts have been made to form configurationallystable derivatives of N-protected/N-substituted alpha-amino aldehydes(see J. Org. Chem. 52:2361-2364, 1987; and J. Am. Chem. Soc.109:236-239, 1987), but such derivatives are not always applicable andthe aldehyde group may still be unstable to long term storage, forexample, due to air oxidation to the corresponding carboxylic acid,trimerization to the corresponding 1,3,5-trioxanes, and the like.

SUMMARY OF THE INVENTION

The present invention relates to a stabilized form ofN-protected/N-substituted alpha-amino aldehydes, in particular,N-protected/N-substituted-beta-amino hydroxy sulfonates, and theirpreparation and use. An N-protected/N-substituted alpha-amino aldehydecan be stored for extended periods in the form of aN-protected/N-substituted-beta-amino hydroxy sulfonate which can bereadily prepared and converted back into the N-protected/N-substitutedalpha-amino aldehyde under mild conditions.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to the preparation and use ofN-protected/N-substituted-beta-amino hydroxy sulfonates, a stabilizedform of N-protected/N-substituted alpha-amino aldehydes, having theformula ##STR1## wherein W represents a cation which is capable offorming a sulfate salt; preferably, W represents a metal cation or aquaternary amine cation; more preferably, W represents a mono- ordivalent metal cation; even more preferably, W represents a cation oflithium, sodium, potassium, calcium, manganese, magnesium, barium,chromium, iron, nickel, cobalt, copper, zinc, cadmium, tin or silver;even more preferably, W represents a cation of lithium, sodium,potassium, calcium, magnesium, barium, iron, nickel, copper or zinc;most preferably, W represents a cation of lithium, sodium or potassium;

R¹ represents alkyl, alkenyl, alkyl substituted with one or more arylradicals, cycloalkenylalkyl, alkanoyl, haloalkanoyl, aroyl,alkoxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl or9-phenylfluoren-9-yl radicals; preferably, R¹ represents alkyl of 1-8carbon atoms, alkenyl of 2-8 carbon atoms, alkyl of 1-3 carbon atomssubstituted with 1-3 aryl radicals, alkyl of 1-3 carbon atomssubstituted with a cycloalkenyl radical of 3-8 ring members, alkanoyl of1-4 alkyl carbon atoms, haloalkanoyl of 1-4 alkyl carbon atoms and 1-3halo radicals, aroyl, alkoxycarbonyl of 1-8 alkyl carbon atoms,arylmethoxycarbonyl, heteroarylmethoxycarbonyl or 9-phenylfluoren-9-ylradicals; more preferably, R¹ represents alkyl of 1-5 carbon atoms,alkenyl of 2-5 carbon atoms, alkyl of 1-2 carbon atoms substituted with1-3 aryl radicals, alkyl of 1-2 carbon atoms substituted with acycloalkenyl radical of 5-6 ring members, alkanoyl of 1-4 alkyl carbonatoms, haloalkanoyl of 1-2 alkyl carbon atoms and 1-3 halo radicals,aroyl, alkoxycarbonyl of 1-5 alkyl carbon atoms, arylmethoxycarbonyl,heteroarylmethoxycarbonyl or 9-phenylfluoren-9-yl radicals; even morepreferably, R¹ represents methyl, ethyl, ethenyl, propenyl, benzyl,diphenylmethyl, naphthylmethyl, trityl, cyclohexenylmethyl, acetyl,butyryl, chloroacetyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl,benzoyl, 2-methylbenzoyl, 2,6-dimethylbenzoyl, 2,4,6-trimethylbenzoyl,2,4,6-triisopropylbenzoyl, methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl, phenylmethoxycarbonyl,(2-methylphenyl)methoxycarbonyl, isobutoxycarbonyl,(4-methylphenyl)methoxycarbonyl, (4-methoxyphenyl)methoxycarbonyl,pyridylmethoxycarbonyl, or 9-phenylfluoren-9-yl radicals; mostpreferably, R¹ represents methyl, ethyl, benzyl, diphenylmethyl,naphthylmethyl, trityl, trifluoroacetyl, tert-butoxycarbonyl,phenylmethoxycarbonyl or (4-methoxyphenyl)methoxycarbonyl radicals;

R² represents hydrogen, alkyl, alkenyl, aralkyl, cycloalkyl,cycloalkenylalkyl or aryl radicals; preferably, R² represents hydrogen,alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkyl of 1-3carbon atoms substituted with an aryl radical, cycloalkyl of 3-8 ringmembers, alkyl of 1-3 carbon atoms substituted with a cycloalkenylradical of 3-8 ring members, or aryl radicals; more preferably, R²represents hydrogen, alkyl of 1-5 carbon atoms, alkenyl of 2-5 carbonatoms, alkyl of 1-2 carbon atoms substituted with an aryl radical,cycloalkyl of 3-6 ring members, alkyl of 1-2 carbon atoms substitutedwith a cycloalkenyl radical of 5-6 ring members, or aryl radicals; evenmore preferably, R² represents methyl, ethyl, ethenyl, propenyl, benzyl,cyclohexenylmethyl or naphthylmethyl radicals; most preferably, R²represents methyl, ethyl or benzyl radicals;

or --NR¹ R² represents heterocyclo or heteroaryl radicals; preferably,--NR¹ R² represents 5-6 ring membered heterocyclo, 5-6 ring memberedheteroaryl, benzo fused 5-6 ring membered heterocyclo or benzo fused 5-6ring membered heteroaryl radicals; more preferably, --NR¹ R² represents5-6 ring membered heterocyclo or benzo fused 5-6 ring memberedheterocyclo radicals; even more preferably, --NR¹ R² representspyrrolidinyl, piperidinyl, pyrrolyl, 2-isoindolinyl, phthalimidyl,succinimidyl or maleimidyl radicals; most preferably, --NR¹ R²represents 2-isoindolinyl, phthalimidyl, succinimidyl or maleimidylradicals;

R³ represents alkyl, alkenyl, alkynyl, haloalkyl, cyanoalkyl,hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, alkylthioalkyl, arylthioalkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl or cycloalkylalkylradicals; preferably, R³ represents alkyl radical of 1 to 5 carbonatoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms,haloalkyl radical of 1 to 5 carbon atoms, cyanoalkyl radical of 1 to 5alkyl carbon atoms, hydroxyalkyl radical of 1 to 5 alkyl carbon atoms,alkoxyalkyl radical of 1 to 5 alkyl carbon atoms and 1-3 alkoxy carbonatoms, aryloxyalkyl radical of 1 to 5 alkyl carbon atoms, alkylthioalkylradical of 1 to 5 alkyl carbon atoms and 1-3 alkylthio carbon atoms,arylthioalkyl radical of 1 to 5 alkyl carbon atoms, aryl radical,aralkyl radical of 1 to 5 alkyl carbon atoms, heteroaralkyl radical of 1to 5 alkyl carbon atoms and 5-6 ring members and benzo fused 5-6 ringmembers, cycloalkyl radical of 3-8 ring members, or cycloalkylalkylradical of 1 to 5 alkyl carbon atoms and 3-8 ring members; morepreferably, R³ represents alkyl radical of 1 to 5 carbon atoms,hydroxyalkyl radical of 1 to 3 alkyl carbon atoms, methoxyalkyl radicalof 1 to 3 alkyl carbon atoms, phenoxyalkyl radical of 1 to 3 alkylcarbon atoms, methylthioalkyl radical of 1 to 3 alkyl carbon atoms,arylthioalkyl radical of 1 to 3 alkyl carbon atoms, aryl radical,aralkyl radical of 1 to 3 alkyl carbon atoms, heteroaralkyl radical of 1to 3 alkyl carbon atoms and 5-6 ring members and benzo fused 5-6 ringmembers, cycloalkyl radical of 5-6 ring members, or cycloalkylalkylradical of 1 to 3 alkyl carbon atoms and 3-6 ring members; even morepreferably, R³ represents methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, hydroxymethyl, hydroxyethyl,methoxyethyl, phenoxymethyl, methylthioethyl, phenylthiomethyl,phenylthioethyl, naphthylthiomethyl, naphthylthioethyl, phenyl,naphthyl, benzyl, 4-fluorobenzyl, 4-methylbenzyl, 4-methoxybenzyl,naphthylmethyl, imidazolylmethyl, indolylmethyl, cyclohexyl orcyclohexylmethyl radicals; most preferably, R³ represents methyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methylthioethyl,phenylthiomethyl, naphthylthiomethyl, benzyl, 4-fluorobenzyl,4-methylbenzyl, 4-methoxybenzyl, naphthylmethyl, imidazolylmethyl orcyclohexylmethyl radicals; or

R² and R³ together with nitrogen atom and the carbon atom to which theyare bonded form a heterocyclo radical; preferably, R² and R³ togetherwith nitrogen atom and the carbon atom to which they are bonded form a5-6 ring membered heterocyclo radical optionally substituted withhydroxy radical; more preferably, R² and R³ together with nitrogen atomand the carbon atom to which they are bonded form pyrrolidinyl,3-hydroxypyrrolidinyl, 4-hydroxypyrrolidinyl, piperidinyl,3-hydroxypiperidinyl, 4-hydroxypiperidinyl or 5-hydroxypiperidinylradicals; and most preferably R² and R³ together with nitrogen atom andthe carbon atom to which they are bonded form pyrrolidinyl orpiperidinyl radicals.

As utilized herein, the term "alkyl", alone or in combination, means astraight-chain or branched-chain alkyl radical containing preferablyfrom 1 to 8 carbon atoms, more preferably from 1 to 5 carbon atoms, mostpreferably 1 to 3 carbon atoms. Examples of such radicals includemethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. The term"alkenyl", alone or in combination, means a straight-chain orbranched-chain hydrocarbon radical having one or more double bonds andcontaining preferably from 2 to 10 carbon atoms, more preferably from 2to 8 carbon atoms, most preferably from 2 to 5 carbon atoms. Examples ofsuitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl,1,4-butadienyl and the like. The term "alkynyl", alone or incombination, means a straight-chain or branched chain hydrocarbonradical having one or more triple bonds and containing preferably from 2to 10 carbon atoms, more preferably from 2 to 5 carbon atoms. Examplesof alkynyl radicals include ethynyl, propynyl (propargyl), butynyl andthe like. The term "alkoxy", alone or in combination, means an alkylether radical wherein the term alkyl is as defined above. Examples ofsuitable alkyl ether radicals include methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.The term "cycloalkyl", alone or in combination, means a saturatedmonocyclic, bicyclic or tricyclic alkyl radical wherein each cyclicmoiety contains preferably from 3 to 8 carbon atom ring members, morepreferably from 3 to 7 carbon atom ring members, most preferably from 5to 6 carbon atom ring members, and which may optionally be a benzo fusedring system which is optionally substituted as defined herein withrespect to the definition of aryl. Examples of such cycloalkyl radicalsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and the like."Bicyclic" and "tricyclic" as used herein are intended to include bothfused ring systems, such as naphthyl and β-carbolinyl, and substitutedring systems, such as biphenyl, phenylpyridyl, naphthyl anddiphenylpiperazinyl. The term "cycloalkylalkyl" means an alkyl radicalas defined above which is substituted by a cycloalkyl radical as definedabove. Examples of such cycloalkylalkyl radicals includecyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl,2-cyclopentylethyl, 2-cyclohexylethyl, cyclobutylpropyl,cyclopentylpropyl, cyclohexylbutyl and the like. The term"cycloalkenyl", alone or in combination, means an cycloalkyl radical asdefined above which contains at least one double bond in the ring and isnon-aromatic in character. The term "cycloalkenylalkyl" meanscycloalkenyl radical as defined above which is attached to an alkylradical as defined above. Examples of such cycloalkenyl andcycloalkenylalkyl radicals include cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, dihydrophenyl, cyclopropenylmethyl,cyclobutenylmethyl, cyclopentenylmethyl, cyclohexenylmethyl,dihydrophenylmethyl, and the like. The term "benzo", alone or incombination, means the divalent radical C₆ H₄ ═ derived from benzene,.The term "aryl", alone or in combination, means a phenyl or naphthylradical which is optionally substituted with one or more substituentsselected from alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano,haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, heterocyclo,alkanoylamino, amido, amidino, alkoxycarbonylamino, N-alkylamidino,alkylamino, dialkylamino, N-alkylamido, N,N-dialkylamido,aralkoxycarbonylamino, alkylthio, alkylsulfinyl, alkylsulfonyl and thelike. Examples of aryl radicals are phenyl, p-tolyl, 4-methoxyphenyl,4-(tert-butoxy)phenyl, 3-methyl-4-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 3-nitrophenyl, 3-aminophenyl, 3-acetamidophenyl,4-acetamidophenyl, 2-methyl-3-acetamidophenyl, 2-methyl-3-aminophenyl,3-methyl-4-aminophenyl, 2-amino-3-methylphenyl,2,4-dimethyl-3-aminophenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl,1-naphthyl, 2-naphthyl, 3-amino-1-naphthyl, 2-methyl-3-amino-1-naphthyl,6-amino-2-naphthyl, 4,6-dimethoxy-2-naphthyl, piperazinylphenyl and thelike. The terms "aralkyl", and "aralkoxy", alone or in combination,means an alkyl or alkoxy radical as defined above in which at least onehydrogen atom is replaced by an aryl radical as defined above, such asbenzyl, benzyloxy, 2-phenylethyl, dibenzylmethyl, hydroxyphenylmethyl,methylphenylmethyl, diphenylmethyl, diphenylmethoxy,4-methoxyphenylmethoxy and the like. The term "aralkoxycarbonyl", aloneor in combination, means a radical of the formula aralkyl-O--C(O)-- inwhich the term "aralkyl" has the significance given above. Examples ofan aralkoxycarbonyl radical are benzyloxycarbonyl and4-methoxyphenylmethoxycarbonyl. The term "aryloxy" means a radical ofthe formula aryl-O-- in which the term aryl has the significance givenabove. The term "alkanoyl", alone or in combination, means an acylradical derived from an alkanecarboxylic acid, examples of which includeacetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like. Theterm "cycloalkylcarbonyl" means an acyl radical of the formulacycloalkyl-C(O)-- in which the term "cycloalkyl" has the significancegive above, such as cyclopropylcarbonyl, cyclohexylcarbonyl,adamantylcarbonyl, 1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl,1-hydroxy-1,2,3,4-tetrahydro-6-naphthoyl and the like. The term"aralkanoyl" means an acyl radical derived from an aryl-substitutedalkanecarboxylic acid such as phenylacetyl, 3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl,4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl,and the like. The term "aroyl" means an acyl radical derived from anarylcarboxylic acid, "aryl" having the meaning given above. Examples ofsuch aroyl radicals include substituted and unsubstituted benzoyl ornapthoyl such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl,4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl,6-carboxy-2-naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl,3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl,3-(benzyloxyformamido)-2-naphthoyl, and the like. The term"heterocyclo," alone or in combination, means a saturated or partiallyunsaturated monocyclic, bicyclic or tricyclic heterocycle radicalcontaining at least one, preferably 1 to 4, more preferably 1 to 2,nitrogen, oxygen or sulfur atom ring members and having preferably 3 to8 ring members in each ring, more preferably 3 to 7 ring members in eachring and most preferably 5 to 6 ring members in each ring. "Heterocyclo"is intended to include sulfones, sulfoxides, N-oxides of tertiarynitrogen ring members, and carbocyclic fused and benzo fused ringsystems. Such heterocyclo radicals may be optionally substituted on atleast one, preferably 1 to 4, more preferably 1 to 2, carbon atoms byhalogen, alkyl, alkoxy, hydroxy, oxo, aryl, aralkyl, heteroaryl,heteroaralkyl, amidino, N-alkylamidino, alkoxycarbonylamino,alkylsulfonylamino and the like, and/or on a secondary nitrogen atom(i.e., --NH--) by hydroxy, alkyl, aralkoxycarbonyl, alkanoyl,heteroaralkyl, phenyl or phenylalkyl, and/or on a tertiary nitrogen atom(i.e., ═N--) by oxido. "Heterocycloalkyl" means an alkyl radical asdefined above in which at least one hydrogen atom is replaced by aheterocyclo radical as defined above, such as pyrrolidinylmethyl,tetrahydrothienylmethyl and the like. The term "heteroaryl", alone or incombination, means an aromatic heterocyclo radical as defined above,which is optionally substituted as defined above with respect to thedefinitions of aryl and heterocyclo. Examples of such heterocyclo andheteroaryl groups are pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiamorpholinyl, pyrrolyl, phthalimide, succinimide,maleimide, imidazolyl (e.g., imidazol 4-yl,1-benzyloxycarbonylimidazol-4-yl, etc.), pyrazolyl, pyridyl, (e.g.,2-(1-piperidinyl)pyridyl and 2-(4-benzyl piperazin-1-yl-1-pyridinyl,etc.), pyrazinyl, pyrimidinyl, furyl, tetrahydrofuryl, thienyl,tetrahydrothienyl and its sulfoxide and sulfone derivatives, triazolyl,oxazolyl, thiazolyl, indolyl (e.g., 2-indolyl, etc.), quinolinyl, (e.g.,2-quinolinyl, 3-quinolinyl, 1-oxido-2-quinolinyl, etc.), isoquinolinyl(e.g., 1-isoquinolinyl, 3-isoquinolinyl, etc.), tetrahydroquinolinyl(e.g., 1,2,3,4-tetrahydro-2-quinolyl, etc.),1,2,3,4-tetrahydroisoquinolinyl (e.g.,1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, etc.), quinoxalinyl,β-carbolinyl, 2-benzofurancarbonyl, 1-,2-,4- or 5-benzimidazolyl,methylenedioxyphen-4-yl, methylenedioxyphen-5-yl, ethylenedioxyphenyl,benzothiazolyl, benzopyranyl, benzofuryl, 2,3-dihydrobenzofuryl,benzoxazolyl, thiophenyl and the like. "Heteroaralkyl" means an alkylradical as defined above in which at least one hydrogen atom is replacedby a heteroaryl radical as defined above, such as pyrrolylmethyl,thienylmethyl, pyridylmethyl, furylmethyl and the like. The term"cycloalkylalkoxycarbonyl", means an acyl group derived from acycloalkylalkoxycarboxylic acid of the formula cycloalkylalkyl-O--COOHwherein cycloalkylalkyl has the meaning given above. The term"heterocycloalkoxycarbonyl" means an acyl radical derived from aheterocycloalkyl-O--COOH wherein heterocyclo has the meaning givenabove. The term "heteroaryloxycarbonyl" means an acyl radical derivedfrom a carboxylic acid represented by heteroaryl-O--COOH whereinheteroaryl has the meaning given above. The terms "halogen" or "halo"mean fluorine, chlorine, bromine or iodine. The term "haloalkanoyl"means an alkanoyl radical having the meaning as defined above whereinone or more hydrogens are replaced with a halogen radical. Examples ofsuch haloalkanoyl radicals include chloroacetyl, fluoroacetyl,difluoroacetyl, trifluoroacetyl, and the like. The term "leaving group"(L) generally refers to groups readily displaceable by a nucleophile,such as an amine, a thiol or an alcohol nucleophile. Such leaving groupsare well known in the art. Examples of such leaving groups include, butare not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole,halides, triflates, tosylates and the like. Preferred leaving groups areindicated herein where appropriate. The term "oxidizing agent" includesa single agent or a mixture of oxidizing reagents. Examples of mixturesof oxidizing reagents include sulfurtrioxide-pyridine/dimethylsulfoxide, oxalyl chloride/dimethyl sulfoxide,acetyl chloride/dimethyl sulfoxide, acetyl anhydride/dimethyl sulfoxide,trifluoroacetyl chloride/dimethyl sulfoxide, toluenesulfonylbromide/dimethyl sulfoxide, phosphorous pentachloride/dimethyl sulfoxideand isobutylchloroformate/dimethyl sulfoxide.

Cations which are capable of forming sulfate salts include metalcations, quaternary amine cations and the like, such as ammonium,tetramethylammonium, tetrabutylammonium, tri-butyloctylammonium,dodecyltrimethylammonium, methyltrihexylammonium,dodecyldimethyl(2-phenoxyethyl)ammonium, tetramethylphosphonium,tetrabutylphosphonium and the like, or cations of lithium, sodium,potassium, rubidium, beryllium, calcium, strontium, manganese,magnesium, barium, chromium, iron, lead, nickel, cobalt, aluminum,cesium, copper, zinc, cadmium, tin, silver, zirconium and the like. Theterm HSO₃ W is intended to include multi-valent cations, such as (HSO₃)₂Ca, (HSO₃)₂ Fe, (HSO₃)₃ Fe, and the like, and cations of mixed salts ofbisulfite, such as (HSO₃) (HO)Ca, (HSO₃) (NO₃)₂ Fe, and the like. Also,the group --SO₃ W is intended to include multi-valent cations, such as(--SO₃)₂ Ca, (--SO₃)₂ Fe, (--SO₃)₃ Fe, and the like, and cations ofmixed salts of bisulfite, such as (--SO₃) (HO)Ca, (--SO₃) (NO₃)₂ Fe, andthe like.

Procedures for preparing the compounds of Formula I are set forth below.It should be noted that the general procedure is shown as it relates topreparation of compounds having the specified stereochemistry, forexample, wherein the absolute stereochemistry about the carbon bonded tothe amino group is designated as (S). However, such procedures aregenerally applicable to those compounds of opposite configuration, e.g.,where the stereochemistry about the carbon bonded to the amino group is(R). In addition, the compounds having the (S) stereochemistry can beutilized to produce those having the (R) stereochemistry. For example, acompound having the (R) stereochemistry can be inverted to the (S)stereochemistry using well-known methods, such as epimerization followedby isolation of the desired racemate.

A general scheme for the preparation ofN-protected/N-substituted-beta-amino hydroxy sulfonates of the presentinvention and their conversion into N-protected/N-substitutedalpha-amino aldehydes is shown in Scheme I below. ##STR2##N-Protected/N-substituted alpha-amino aldehydes can be reacted with atleast one equivalent of the bisulfite salt HSO₃ W, preferably at anequivalence ratio within the range of about 1:1 to about 1:10, morepreferably about 1:1 to about 1:5, and most preferably about 1:2 toabout 1:5, in the appropriate solvent system, preferably, a mixture ofwater and an organic solvent such as ethyl acetate, tetrahydrofuran,isopropyl acetate, methyl isobutyl ketone, methyl ethyl ketone, acetone,dimethoxyethane, dimethoxymethane, dioxane, methyl tert-butylether andthe like, to form the corresponding N-protected/N-substituted-beta-aminohydroxy sulfonates.

The aldehyde can be readily recovered by reacting the salt with aqueousbase (pH>7.0), more preferably, at a pH in the range of about 7.5 toabout 10 and most preferably, in the range of about 8 to about 9,followed by extraction with the appropriate organic solvent such asethyl acetate and the like. The aqueous base is preferably aqueoussodium carbonate, potassium carbonate, sodium hydroxide, potassiumhydroxide, ammonimum hydroxide, magnesium oxide, calcium oxide, and thelike. The addition of an equilibrium exchange agent, such asformaldehyde, acetaldehyde, chloroacetaldehyde, benzaldehyde and thelike, and preferably, a water soluble equilibrium exchange agent, suchas formaldehyde, will assist in the reversion of the sulfonate into thecorresponding aldehyde.

N-Protected/N-substituted alpha-amino aldehydes can be preparedeconomically and safely in small or large scales from either thecorresponding amino acids or amino alcohols, which are commerciallyavailable or readily prepared from commercially available startingmaterials, using methods well known in the art.

N-Protected/N-substituted alpha-amino alcohol of the Formula II ##STR3##wherein R¹, R² and R³ are described above, can be prepared from thecorresponding amino acids or amino alcohols of Formulas III and IV##STR4## The amine group in each case can be alkylated in an appropriatesolvent in the presence of base by the addition of suitable alkylatingagents such as R² L and/or R¹ L, wherein L is a leaving group selectedfrom halo, tosylate, and the like, and R¹ and R² are as defined above. Apreferred method of forming substituted amines involves the aqueousaddition of about 3 moles of organic halide to the amino acid or about 2moles to the amino alcohol. In an more preferred method, the alkylationoccurs at 50° C. to 80° C. with potassium carbonate in water,ethanol/water or denatured ethanol/water. Additives such as sodium orpotassium bromide, sodium or potassium iodide can catalyze or acceleratethe rate of amine alkylation, especially when benzyl chloride was usedas the nitrogen alkylating agent.

Alternate bases used in alkylation include sodium hydroxide, sodiumbicarbonate, potassium hydroxide, lithium hydroxide, potassiumcarbonate, sodium carbonate, cesium hydroxide, magnesium hydroxide,calcium hydroxide or calcium oxide, or tertiary amine bases such astriethylamine, diisopropylethylamine, N-methylpiperidine, pyridine,dimethylaminopyridine and azabicyclononane. Reactions can be homogenousor heterogenous. Suitable solvents are water and protic solvents orsolvents miscible with water, such as methanol, ethanol, isopropylalcohol, tetrahydrofuran and the like, with or without added water.Dipolar aprotic solvents may also be used with or without added proticsolvents including water. Examples of dipolar aprotic solvents includeacetonitrile, dimethylformamide, dimethyl acetamide, acetamide,tetramethyl urea and its cyclic analog, dimethylsulfoxide,N-methylpyrrolidone, sulfolane, nitromethane and the like. Reactiontemperature can range between about -20° to 100° C. with the preferredtemperature of about 25-85° C. The reaction may be carried out under aninert atmosphere such as nitrogen or argon, or normal or dry air, underatmospheric pressure or in a sealed reaction vessel under positivepressure. The most preferred alkylating agents are benzyl bromide orbenzyl chloride or monosubstituted aralkyl halides or polysubstitutedaralkyl halides. Sulfate or sulfonate esters are also suitable reagentsto provide the corresponding benzyl analogs and they can be preformedfrom the corresponding benzyl alcohol or formed in situ by methods wellknown to those skilled in the art. Trityl, benzhydryl, substitutedtrityl and substituted benzhydryl groups, independently, are alsoeffective amine protecting groups as are allyl and substituted allylgroups. Their halide derivatives can also be prepared from thecorresponding alcohols by methods well known to those skilled in the artsuch as treatment with thionyl chloride or bromide or with phosphorustri- or pentachloride, bromide or iodide or the corresponding phosphoryltrihalide. 1,2-Bis-substituted alkylene halides or sulfonate esters andbenzo fused derivatives thereof can be used to form a nitrogencontaining heteroaryl or heterocyclo containing compounds. Phasetransfer catalysis wherein the amine and the alkylating agent arereacted with base in a solvent mixture in the presence of a phasetransfer reagent, catprost or promoter. The mixture can consist of, forexample, toluene, benzene, ethylene dichloride, cyclohexane, methylenechloride or the like with water or a aqueous solution of an organicwater miscible solvent such as THF. Examples of phase transfer catalystsor reagents include tetrabutylammonium chloride or iodide or bromide,tetrabutylammonium hydroxide, tri-butyloctylammonium chloride,dodecyltrihexylammonium hydroxide, methyltrihexylammonium chloride andthe like.

Alternatively, the amino group can be reductively alkylated with analdehyde or ketone to introduce the R¹ and/or R² groups. For example,when R¹ and R² represent benzyl groups, treatment of the amine withbenzaldehyde under reductive amination conditions affords the desiredN,N-dibenzylamine intermediate. Similarly, when R² is an cyclohexylgroup, treatment the amine with cyclohexanone under reductive aminationconditions affords the desired N-cyclohexylamine intermediate. Otheraldehydes and ketones can be used to introduce various R¹ and R² groups.Reductive amination can be performed using a variety of reactionconditions well-known to those skilled in the art. For example, thereductive amination of the amine with an aldehyde can be carried outwith a reducing agent such as sodium cyanoborohydride or sodiumborohydride in a suitable solvent, such as methanol, ethanol,tetrahydrofuran and the like. Alternatively, the reductive amination canbe carried out using hydrogen in the presence of a catalyst such aspalladium or platinum, palladium on carbon or platinum on carbon, orvarious other metal catalysts known to those skilled in the art, in asuitable solvent such as methanol, ethanol, tetrahydrofuran, ethylacetate, toluene and the like.

Alternatively, N-protected/N-substituted alpha-amino alcohol and acidscan be prepared by reduction of a Schiff Base, carbinolamine or enamineor reduction of an acylated amine derivative. Reducing agents includemetals platinum, palladium, palladium hydroxide, palladium on carbon,platinum oxide, rhodium and the like! with hydrogen gas or hydrogentransfer molecules such as cyclohexene or cyclohexadiene or hydrideagents such as lithium aluminumhydride, sodium borohydride, lithiumborohydride, sodium cyanoborohydride, diisobutylaluminum hydride orlithium tri-tert-butoxyaluminum hydride.

The N-protected/N-substituted alpha-amino alcohol can then be preparedby reduction of the corresponding N-protected/N-substituted alpha-aminoacid of formula ##STR5## or an ester or amide thereof. This process isparticularly suitable when hydroxy groups are present in the molecule.The hydroxy groups can be selectively protected, using well knownhydroxy protecting groups, prior to formation of theN-protected/N-substituted alpha-amino alcohol and thus allowingselective oxidation of the alcohol group to an aldehyde moiety. Thehydroxy protecting groups are then removed after formation of thealdehyde. The reduction can be accomplished using a variety of reducingreagents and conditions. Reducing agents include metals platinum,palladium, palladium hydroxide, palladium on carbon, platinum oxide,rhodium and the like! with hydrogen gas or hydrogen transfer moleculessuch as cyclohexene or cyclohexadiene, or hydride agents such as lithiumaluminumhydride, diborane.tetrahydrofuran, sodium borohydride, lithiumborohydride, sodium cyanoborohydride, diisobutylaluminum hydride orlithium tri-tert-butoxyaluminum hydride. Preferred reducing agentsinclude lithium aluminum hydride, lithium borohydride, sodiumborohydride, borane, lithium tri-ter-butoxyaluminum hydride, anddiborane.tetrahydrofuran. Most preferably, the reducing agent is lithiumaluminum hydride, diborane.tetrahydrofuran or diisobutylaluminum hydride(DiBAL-H) in toluene.

The above preparation of N-protected/N-substituted alpha-amino alcoholis applicable to mixtures of optical isomers as well as resolvedcompounds. If a particular optical isomer is desired, it can be selectedby the choice of starting material, e.g., L-phenylalanine,D-phenylalanine, L-phenylalaninol, D-phenylalaninol,D-hexahydrophenylalaninol and the like, or resolution can occur atintermediate or final steps. Chiral auxiliaries such as one or twoequivalents of camphor sulfonic acid, citric acid, camphoric acid,2-methoxyphenylacetic acid and the like can be used to form salts,esters or amides of the starting materials of this invention. Thesecompounds or derivatives can be crystallized or separatedchromatographically using either a chiral or achiral column as is wellknown to those skilled in the art.

Purification of the N-protected/N-substituted alpha-amino alcohol bychromatography is possible. In the preferred purification method thealpha amino alcohol can be purified by an acid quench of the reaction,such as with hydrochloric acid, and the resulting salt can be filteredoff as a solid and the amino alcohol can be liberated such as byacid/base extraction.

The N-protected/N-substituted alpha-amino alcohol is oxidized to form achiral amino aldehyde of the formula ##STR6## Acceptable oxidizingreagents include, for example, sulfur trioxide-pyridine complex andDMSO, oxalyl chloride and DMSO, acetyl chloride or anhydride and DMSO,trifluoroacetyl chloride or anhydride and DMSO, methanesulfonyl chlorideand DMSO or tetrahydrothiaphene-S-oxide, toluenesulfonyl bromide andDMSO, trifluoromethanesulfonyl anhydride (triflic anhydride) and DMSO,phosphorus pentachloride and DMSO, dimethylphosphoryl chloride and DMSOand isobutylchloroformate and DMSO. The oxidation conditions reported inAngew Chem., 99:1186, 1987 (Angew Chem. Int. Ed. Engl., 26:1141, 1987),and J. Org. Chem. 43:2480-2482, 1978 employed oxalyl chloride and DMSO;and in J. Am. Chem. Soc., 89:5505, 1967, Chem. Pharm. Bull.30:1921-1924, 1982, and J. Org. Chem. 47:3016-3018, 1982, employed SO₃/Pyridine complex in methylene chloride or DMSO and triethylamine. Thepreferred oxidation method is sulfur trioxide pyridine complex intriethylamine and DMSO at room temperature. The oxidation reaction maybe carried out under an inert atmosphere such as nitrogen or argon, ornormal or dry air, under atmospheric pressure or in a sealed reactionvessel under positive pressure. Preferred is a nitrogen atmosphere.Alternative amine bases include, for example, tri-butyl amine,tri-isopropyl amine, N-methylpiperidine, N-methyl morpholine,azabicyclononane, diisopropylethylamine, 2,2,6,6-tetramethylpiperidine,N,N-dimethylaminopyridine, or mixtures of these bases. Triethylamine isa preferred base. Alternatives to pure DMSO as solvent include mixturesof DMSO with non-protic or halogenated solvents such as tetrahydrofuran,ethyl acetate, toluene, xylene, dichloromethane, ethylene dichloride andthe like. Dipolar aprotic co-solvents include acetonitrile,dimethylformamide, dimethylacetamide, acetamide, tetramethyl urea andits cyclic analog, N-methylpyrrolidone, sulfolane and the like.

Two additional methods of obtaining the nitrogen protected aldehydeinclude oxidation of the corresponding alcohol with bleach in thepresence of a catalytic amount of 2,2,6,6-tetramethyl-1-pyridyloxy freeradical. In a second method, oxidation of the alcohol to the aldehyde isaccomplished by a catalytic amount of tetrapropylammonium perruthenatein the presence of N-methylmorpholine-N-oxide.

Alternatively, the N-protected/N-substituted alpha-amino aldehyde can beprepared directly from the corresponding N-protected/N-substitutedalpha-amino acid ester or amide by hydride reduction sodium amalgam withHCl in ethanol or lithium or sodium or potassium or calcium in ammonia.The reaction temperature may be from about -20° C. to about 45° C., andpreferably from abut 5° C. to about 25° C. Hydride transfer is anadditional method of aldehyde synthesis under conditions where aldehydecondensations are avoided, cf, Oppenauer Oxidation. Alternatively, theacid halide derivative, such as acid chloride, can be reduced withhydrogen and a catalyst such as Pd on barium carbonate or bariumsulphate, with or without an additional catalyst moderating agent suchas sulfur or a thiol (Rosenmund Reduction). Such methods are preferredwhen hydroxy groups are present in the molecule. This approach willgenerally avoid the necessity of protecting and deprotecting the alcoholgroups.

Scheme II is an illustrative example of alternative preparation methodsof 2S- bis(phenylmethyl)amino!-3-phenylpropanal. ##STR7## The synthesisstarts from L-phenylalanine. The aldehyde is prepared in three stepsfrom L-phenylalanine or L-phenylalaninol. L-Phenylalanine is convertedto the N,N-dibenzylamino acid benzyl ester using benzyl bromide underaqueous conditions. The reduction of benzyl ester is carried out usingdiisobutylaluminum hydride (DIBAL-H) in toluene. Instead of purificationby chromatography, the product is purified by an acid (hydrochloricacid) quench of the reaction, the hydrochloride salt is filtered off asa white solid and then liberated by an acid/base extraction. After onerecrystallization, chemically and optically pure alcohol is obtained.Alternately, and preferably, the alcohol can be obtained in one step in88% yield by the benzylation of L-phenylalaninol using benzylbromideunder aqueous conditions. The oxidation of alcohol to aldehyde is alsomodified to allow for more convenient operation during scaleup. Insteadof the standard Swern procedures using oxalyl chloride and DMSO inmethylene chloride at low temperatures, sulfur trioxide-pyridine/DMSOwas employed (J. Am. Chem. Soc., 89:5505, 1967) which can beconveniently performed at room temperature to give excellent yields ofthe desired aldehyde with high chemical and enantiomer purity which doesnot require purification.

Scheme III illustrates the preparation of 2S- (tert-butoxycarbonyl)(phenylmethyl)amino!-3-phenylpropanal from L-phenylalaninol, where BOCis tert-butoxycarbonyl and Bn is benzyl. ##STR8##

Scheme IV illustrates the preparation ofN-protected/N-substituted-beta-amino hydroxy sulfonates of the presentinvention where R² and R³ together with nitrogen atom and the carbonatom to which they are bonded form a heterocyclo radical (n=0-1).##STR9##

The chemical reactions described above are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilyprepared from known starting materials.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

All reagents were used as received without purification. All proton andcarbon NMR spectra were obtained on either a Varian VXR-300 or VXR-400nuclear magnetic resonance spectrometer.

The following Examples illustrate the preparation of inhibitor compoundsof the present invention and intermediates useful in preparing theinhibitor compounds of the present invention.

EXAMPLE 1 ##STR10## 2S- Bis(phenylmethyl)amino!-3-phenylpropanol

METHOD 1

Step 1: Benzylation of L-Phenylalanine

A solution of L-phenylalanine (50.0 g, 0.302 mol), sodium hydroxide(24.2 g, 0.605 mol) and potassium carbonate (83.6 g, 0.605 mol) in water(500 mL) was heated to 97° C. Benzyl bromide (108.5 mL, 0.605 mol) wasthen slowly added (addition time--25 min). The mixture was stirred at97° C. for 30 minutes under a nitrogen atmosphere. The solution wascooled to room temperature and extracted with toluene (2×250 mL). Thecombined organic layers were washed with water and brine, dried overmagnesium sulfate, filtered and concentrated to an oil. The identity ofthe product was confirmed as follows. Analytical TLC (10% ethylacetate/hexane, silica gel) showed major component at Rf value=0.32 tobe the desired tribenzylated compound,N,N-bis(phenylmethyl)-L-phenylalanine phenylmethyl ester. This compoundcan be purified by column chromatography (silica gel, 15% ethylacetate/hexanes). Usually the product is pure enough to be used directlyin the next step without further purification. ¹ H NMR spectrum was inagreement with published literature. ¹ H NMR (CDCl₃) ∂, 3.00 and 3.14(ABX-system, 2H, J_(AB) =14.1 Hz, J_(AX) =7.3 Hz and J_(BX) =5.9 Hz),3.54 and 3.92 (AB-System, 4H, J_(AB) =13.9 Hz), 3.71 (t, 1H, J=7.6 Hz),5.11 and 5.23 (AB-System, 2H, J_(AB) =12.3 Hz), and 7.18 (m, 20H). EIMS:m/z 434 (M-1).

Step 2: 2S- Bis(phenylmethyl)amino!-3-phenylpropanol

N,N-Bis(phenylmethyl)-L-phenylalanine phenylmethyl ester (0.302 mol)from the previous reaction was dissolved in toluene (750 mL) and cooledto -55° C. A 1.5M solution of DIBAL in toluene (443.9 mL, 0.666 mol) wasadded at a rate to maintain the temperature between -55 to -50° C.(addition time--1 hr). The mixture was stirred for 20 minutes under anitrogen atmosphere and then quenched at -55° C. by the slow addition ofmethanol (37 ml). The cold solution was then poured into cold (5° C.)1.5N HCl solution (1.8 L). The precipitated solid (approx. 138 g) wasfiltered off and washed with toluene. The solid material was suspendedin a mixture of toluene (400 mL) and water (100 ml). The mixture wascooled to 5° C. and treated with 2.5N NaOH (186 mL) and then stirred atroom temperature until solid dissolved. The toluene layer was separatedfrom the aqueous phase and washed with water and brine, dried overmagnesium sulfate, filtered and concentrated to a volume of 75 mL (89g). Ethyl acetate (25 mL) and hexane (25 mL) were added to the residueupon which the desired alcohol product began to crystallize. After 30min, an additional 50 mL hexane were added to promote furthercrystallization. The solid was filtered off and washed with 50 mL hexaneto give 34.9 g of first crop product. A second crop of product (5.6 g)was isolated by refiltering the mother liquor. The two crops werecombined and recrystallized from ethyl acetate (20 mL) and hexane (30mL) to give 40 g of 2S- bis(phenylmethyl)amino!-3-phenylpropanol, 40%yield from L-phenylalanine. An additional 7 g (7%) of product can beobtained from recrystallization of the concentrated mother liquor. TLCof product Rf=0.23 (10% ethyl acetate/hexane, silica gel);¹ H NMR(CDCl₃) ∂2.44 (m, 1H,), 3.09 (m, 2H), 3.33 (m, 1H), 3.48 and 3.92(AB-System, 4H, J_(AB) =13.3 Hz), 3.52 (m, 1H) and 7.23 (m, 15H); a!_(D)25+42.4 (c 1.45, CH₂ Cl₂); DSC 77.67° C.; Anal. Calcd.for C₂₃ H₂₅ ON: C,83.34; H, 7.60; N, 4.23. Found: C, 83.43; H, 7.59; N, 4.22. HPLC onchiral stationary phase: Cyclobond I SP column (250×4.6 mm I.D.), mobilephase: methanol/triethyl ammonium acetate buffer pH 4.2 (58:42, v/v),flow-rate of 0.5 ml/min, detection with detector at 230 nm and atemperature of 0° C. Retention time: 11.25 min., retention time of thedesired product enantiomer: 12.5 min.

METHOD 2

Preparation of 2S- Bis(phenylmethyl)amino!-3-phenylpropanol

L-phenylalaninol (176.6 g, 1.168 mol) was added to a stirred solution ofpotassium carbonate (484.6 g, 3.506 mol) in 710 mL of water. The mixturewas heated to 65° C. under a nitrogen atmosphere. A solution of benzylbromide (400 g, 2.339 mol) in 3A ethanol (305 mL) was added at a ratethat maintained the temperature between 60-68° C. The biphasic solutionwas stirred at 65° C. for 55 min and then allowed to cool to 10° C. withvigorous stirring. The oily product solidified into small granules. Theproduct was diluted with 2.0 L of tap water and stirred for 5 minutes todissolve the inorganic by products. The product was isolated byfiltration under reduced pressure and washed with water until the pH is7. The crude product obtained was air dried overnight to give a semi-drysolid (407 g) which was recrystallized from 1.1 L of ethylacetate/heptane (1:10 by volume). The product was isolated by filtration(at -8° C. ), washed with 1.6 L of cold (-10° C. ) ethyl acetate/heptane(1:10 by volume) and air-dried to give 339 g (88% yield) of 2S-Bis(phenylmethyl)amino!-3-phenylpropanol, mp 71.5-73.0° C. More productcan be obtained from the mother liquor if necessary. The otheranalytical characterization was identical to compound prepared asdescribed in Method 1.

EXAMPLE 2 ##STR11## Preparation of 2-S-Bis(phenylmethyl)amino!-3-phenylpropanal

METHOD 1

2S- Bis(phenylmethyl)amino!-3-phenylpropanol (200 g, 0.604 mol) wasdissolved in triethylamine (300 mL, 2.15 mol). The mixture was cooled to12° C. and a solution of sulfur trioxide/pyridine complex (380 g, 2.39mol) in DMSO (1.6 L) was added at a rate to maintain the temperaturebetween 8-17° C. (addition time--1.0 h). The solution was stirred atambient temperature under a nitrogen atmosphere for 1.5 hour at whichtime the reaction was complete by TLC analysis (33% ethylacetate/hexane, silica gel). The reaction mixture was cooled with icewater and quenched with 1.6 L of cold water (10-15° C.) over 45 minutes.The resultant solution was extracted with ethyl acetate (2.0 L), washedwith 5% citric acid (2.0 L), and brine (2.2 L), dried over MgSO₄ (280 g)and filtered. The solvent was removed on a rotary evaporator at 35-40°C. and then dried under vacuum to give 198.8 g of 2S-Bis(phenylmethyl)amino!-3-phenylpropanal as a pale yellow oil (99.9%).The crude product obtained was pure enough to be used directly in thenext step without purification. The analytical data of the compound wereconsistent with the published literature. a!_(D) 25=-92.9° (c 1.87, CH₂Cl₂); ¹ H NMR (400 MHz, CDCl₃) ∂, 2.94 and 3.15 (ABX-System, 2H, J_(AB)=13.9 Hz, J_(AX) =7.3 Hz and J_(BX) =6.2 Hz), 3.56 (t, 1H, 7.1 Hz), 3.69and 3.82 (AB-System, 4H, J_(AB) =13.7 Hz), 7.25 (m, 15H) and 9.72 (s,1H); HRMS calcd for (M+1) C₂₃ H₂₄ NO 330.450, found: 330.1836. Anal.Calcd. for C₂₃ H₂₃ ON: C, 83.86; H, 7.04; N, 4.25. Found: C, 83.64; H,7.42; N, 4.19. HPLC on chiral stationary phase:(S,S) Pirkle-Whelk-O 1column (250×4.6 mm I.D.), mobile phase: hexane/isopropanol (99.5:0.5,v/v), flow-rate: 1.5 ml/min, detection with UV detector at 210 nm.Retention time of the desired S-isomer: 8.75 min., retention time of theR-enantiomer 10.62 min.

METHOD 2

A solution of oxalyl chloride (8.4 ml, 0.096 mol) in dichloromethane(240 ml) was cooled to -74° C. A solution of DMSO (12.0 ml, 0.155 mol)in dichloromethane (50 ml) was then slowly added at a rate to maintainthe temperature at -74° C. (addition time˜1.25 hr). The mixture wasstirred for 5 min. followed by addition of a solution of 2S-bis(phenylmethyl)amino!-3-phenylpropanol (0.074 mol) in 100 ml ofdichloromethane (addition time -20 min., temp. -75° C. to -68° C.). Thesolution was stirred at -78° C. for 35 minutes under a nitrogenatmosphere. Triethylamine (41.2 ml, 0.295 mol) was then added over 10min. (temp. -78° to -68° C.) upon which the ammonium salt precipitated.The cold mixture was stirred for 30 min. and then water (225 ml) wasadded. The dichloromethane layer was separated from the aqueous phaseand washed with water, brine, dried over magnesium sulfate, filtered andconcentrated. The residue was diluted with ethyl acetate and hexane andthen filtered to further remove the ammonium salt. The filtrate wasconcentrated to give 2S- Bis(phenylmethyl)amino!-3-phenylpropanal. Thealdehyde was generally used without purification.

METHOD 3

To a mixture of 1.0 g (3.0 mmoles) of 2S-bis(phenylmethyl)amino!-3-phenylpropanol 0.531 g (4.53 mmoles) ofN-methylmorpholine, 2.27 g of molecular sieves (4A) and 9.1 mL ofacetonitrile was added 53 mg (0.15 mmoles) of tetrapropylammoniumperruthenate (TPAP). The mixture was stirred for 40 minutes at roomtemperature and concentrated under reduced pressure. The residue wassuspended in 15 mL of ethyl acetate, filtered through a pad of silicagel. The filtrate was concentrated under reduced pressure to give aproduct containing approximately 50% of 2S-Bis(phenylmethyl)amino!-3-phenylpropanal as a pale yellow oil.

METHOD 4

To a solution of 1.0 g (3.02 mmoles) of 2S-bis(phenylmethyl)amino!-3-phenylpropanol in 9.0 mL of toluene was added4.69 mg(0.03 mmoles) of 2,2,6,6-tetramethyl-1-piperidinyloxy, freeradical (TEMPO), 0.32 g (3.11 mmoles) of sodium bromide, 9.0 mL of ethylacetate and 1.5 mL of water. The mixture was cooled to 0° C. and anaqueous solution of 2.87 mL of 5% household bleach containing 0.735g(8.75 mmoles) of sodium bicarbonate and 8.53 mL of water was addedslowly over 25 minutes. The mixture was stirred at 0° C. for 60 minutes.Two more additions (1.44 mL each) of bleach was added followed bystirring for 10 minutes. The two phase mixture was allowed to separate.The aqueous layer was extracted twice with 20 mL of ethyl acetate. Thecombined organic layer was washed with 4.0 mL of a solution containing25 mg of potassium iodide and water(4.0 mL), 20 mL of 10% aqueous sodiumthiosulfate solution and then brine solution. The organic solution wasdried over magnesium sulfate, filtered and concentrated under reducedpressure to give 1.34 g of crude oil containing a small amount of 2S-bis(phenylmethyl)amino!-3-phenylpropanal.

METHOD 5

Following the same procedures as described in Method 1 except 3.0equivalents of sulfur trioxide pyridine complex was used and 2S-bis(phenylmethyl)amino!-3-phenylpropanal was isolated in comparableyields.

EXAMPLE 3 ##STR12## Preparation of N-Benzyl-L-phenylalaninol

METHOD 1

L-Phenylalaninol (89.51 g, 0.592 moles) was dissolved in 375 mL ofmethanol under inert atmosphere, 35.52 g (0.592 moles) of glacial aceticacid and 50 mL of methanol was added followed by a solution of 62.83 g(0.592 moles) of benzaldehyde in 100 mL of methanol. The mixture wascooled to approximately 15° C. and a solution of 134.6 g (2.14 moles) ofsodium cyanoborohydride in 700 mL of methanol was added in approximately40 minutes, keeping the temperature between 15° C. and 25° C. Themixture was stirred at room temperature for 18 hours. The mixture wasconcentrated under reduced pressure and partitioned between 1 L of 2Mammonium hydroxide solution and 2 L of ether. The ether layer was washedwith 1 L of 1M ammonium hydroxide solution, twice with 500 mL water, 500mL of brine and dried over magnesium sulfate for 1 hour. The ether layerwas filtered, concentrated under reduced pressure and the crude solidproduct was recrystallized from 110 mL of ethyl acetate and 1.3 L ofhexane to give 115 g (81% yield) of N-benzyl-L-phenylalaninol as a whitesolid.

METHOD 2

L-Phenylalaninol (5 g, 33 mmoles) and 3.59 g (33.83 mmoles) ofbenzaldehyde were dissolved in 55 mL of 3A ethanol under inertatmosphere in a Parr shaker and the mixture was warmed to 60° C. for 2.7hours. The mixture was cooled to approximately 25° C. and 0.99 g of 5%platinum on carbon was added and the mixture was hydrogenated at 60 psiof hydrogen and 40° C. for 10 hours. The catalyst was filtered off, theproduct was concentrated under reduced pressure and the crude solidproduct was recrystallized from 150 mL of heptane to give 3.83 g(48%yield) of N-benzyl-L-phenylalaninol as a white solid.

EXAMPLE 4 ##STR13## Preparation ofN-(tert-Butoxycarbonyl)-N-benzyl-L-phenylalaninol

N-Benzyl-L-phenylalaninol (2.9 g, 12 mmoles) was dissolved in 3 mL oftriethylamine and 27 mL of methanol and 5.25 g (24.1 mmoles) ofdi-tert-butyl dicarbonate was added. The mixture was warmed to 60° C.for 35 minutes and concentrated under reduced pressure. The residue wasdissolved in 150 mL of ethyl acetate and washed twice with 10 mL ofcold(0-5° C.), dilute hydrochloric acid (pH 2.5 to 3), 15 mL of water,10 mL of brine, dried over magnesium sulfate, filtered and concentratedunder reduced pressure. The crude product oil was purified by silica gelchromatography (ethyl acetate:hexane, 12:3 as eluting solvent) to give3.98 g (97% yield) of colorless oil.

EXAMPLE 5 ##STR14## Preparation ofN-(t-Butoxycarbonyl)-N-benzyl-L-phenylalaninal

METHOD 1

To a solution of 0.32 g(0.94 mmoles) ofN-(tert-butoxycarbonyl)-N-benzyl-L-phenylalaninol in 2.8 mL of toluenewas added 2.4 mg (0.015 mmoles) of 2,2,6,6-tetramethyl-1-piperidinyloxy,free radical (TEMPO), 0.1 g (0.97 mmoles) of sodium bromide, 2.8 mL ofethyl acetate and 0.34 mL of water. The mixture was cooled to 0° C. andan aqueous solution of 4.2 mL of 5% household bleach containing 0.23 g(3.0 mL, 2.738 mmoles) of sodium bicarbonate was added slowly over 30minutes. The mixture was stirred at 0° C. for 10 minutes. Three moreadditions (0.4 mL each) of bleach was added followed by stirring for 10minutes after each addition to consume all the stating material. The twophase mixture was allowed to separate. The aqueous layer was extractedtwice with 8 mL of toluene. The combined organic layer was washed with1.25 mL of a solution containing 0.075 g of potassium iodide, sodiumbisulfate (0.125 g) and water (1.1 mL), 1.25 mL of 10% aqueous sodiumthiosulfate solution, 1.25 mL of pH 7 phosphate buffer and 1.5 mL ofbrine solution. The organic solution was dried over magnesium sulfate,filtered and concentrated under reduced pressure to give 0.32 g (100%yield) of N-(tert-butoxycarbonyl)-N-benzyl-L-phenylalaninal.

METHOD 2

To a solution of 2.38 g (6.98 mmoles) ofN-(tert-butoxycarbonyl)-N-benzyl-L-phenylalaninol in 3.8 mL (27.2mmoles) of triethylamine at 10° C. was added a solution of 4.33 g (27.2mmoles) of sulfur trioxide pyridine complex in 17 mL of dimethylsulfoxide. The mixture was warmed to room temperature and stirred forone hour. Water (16 mL) was added and the mixture was extracted with 20mL of ethyl acetate. The organic layer was washed with 20 mL of 5%citric acid, 20 mL of water, 20 mL of brine, dried over magnesiumsulfate and filtered. The filtrate was concentrated under reducedpressure to give 2.37 g (100% yield) ofN-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninal.

EXAMPLE 6 ##STR15## Preparation of 2S-bis(phenylmethyl)amino!-1-hydroxy-3-phenylpropylsulfonic acid, sodiumsalt

2S- Bis(phenylmethyl)amino!-3-phenylpropanal, which was stored at -80°C., was warmed from -80° C. until it became a syrup. Fifty grams (0.1518mol) was dissolved in 200 mL of ethyl acetate at room temperature undera nitrogen atmosphere. Sodium bisulfite (NaHSO₃), 49.8 g (0.4544 mol),in 200 mL of water was added in a slow stream to the aldehyde solution.Vigorous stirring was maintained during the addition and the reaction.After about one hour, the ethyl acetate layer was separated and thesolvent partially removed under vacuum on a rotary evaporator to providea crystalline solid. The ethyl acetate solution was recombined with thesodium bisulfite and the ethyl acetate removed under vacuum. Ethylacetate was added to the residue in 25 mL portions for a total of 75 mLand the white solid thus obtained separated by filtration. The solid waswashed with ethyl acetate and dried under a nitrogen atmosphere andvacuum to yield 16 grams of 2S-bis(phenylmethyl)amino!-1-hydroxy-3-phenylpropylsulfonic acid, sodiumsalt as a white solid. The assigned structure was confirmed bycombustion analysis and infrared (IR) spectroscopy as a potassiumbromide pellet. Combustion Analysis: Calculated for C₂₃ H₂₄ NO₄ SNa(433.50); C=63.73%, H=5.58%, N=3.23%, S=7.40%; Found: C=65.94%, 65.73%,H=6.27%, 6.28% N=3.35%, 3.26%, S=8.04%. There was no aldehyde carbonylgroup in the IR spectrum.

EXAMPLE 7 ##STR16## Preparation of 2S-bis(phenylmethyl)amino!-3-phenylpropanal from 2S-bis(phenylmethyl)amino!-1-hydroxy-3-phenylpropylsulfonic acid, sodiumsalt

2S- Bis(phenylmethyl)amino!-1-hydroxy-3-phenylpropyl sulfonic acid,sodium salt (5 grams) was treated with stirring with an aqueous solutionof 5 grams of potassium carbonate in 50 mL of water at room temperature.The aqueous solution was extracted once with a 50 mL portion of ethylacetate. The organic solvent solutions were combined and removed underreduced pressure. The residue was dissolved in the tetrahydrofuran(THF), filtered through a cotton filter plug and the solvent removedunder reduced pressure. The residue was again dissolved in THF and thesolvent removed under reduced pressure to provide 4.1 grams of 2S-bis(phenylmethyl)amino!-3-phenylpropanal as a colorless oil whoseidentity was confirmed by high performance liquid chromatography (HPLC)using Whatman Partisil 5 column 25 cm in length with a 4.6 mm i.d. atambient (room) temperature. Detection was by a UV detector at 215nanometers and elution with a mobil phase of 95% hexane and 5%tert-butylmethyl ether at a flow rate of 1.0 mL per minute. The sampleswere placed on the column diluted in 90% hexane, 5% isopropanol and 5%tert-butylmethyl ether.

EXAMPLE 8

Following the procedures of the previous Examples, the compounds setforth in Tables 1 through 13 can be prepared.

                  TABLE 1    ______________________________________    1 #STR17##    Entry      R.sup.3             W    ______________________________________    1          isobutyl            Na    2          butyl               Na    3          sec-butyl           K    4          ethyl               Na    5          benzyl              Li    6          4-hydroxyphenylmethyl                                   Na    7          hydroxymethyl       Na    8          2-(methylthio)ethyl K    9          4-(BOC-amino)butyl  Na    10         aminocarbonylmethyl Li    11         N-BOC-imidazol-2-ylmethyl                                   Na    12         4-hydroxyphenyl     Na    13         hydrogen            Na    14         methyl              Na    15         4-fluorophenylmethyl                                   K    16         cyanomethyl         K    17         bromomethyl         Na    18         trifluoromethyl     Li    19         phenoxymethyl       K    20         phenylthiomethyl    Na    21         phenyl              Li    22         4-pyridyl           K    23         cyclohexyl          Na    24         cyclohexylmethyl    K    ______________________________________

                  TABLE 2    ______________________________________    2 #STR18##    Entry      R.sup.3             W    ______________________________________    1          isobutyl            Na    2          butyl               Na    3          sec-butyl           K    4          ethyl               Na    5          benzyl              Li    6          4-hydroxyphenylmethyl                                   Na    7          hydroxymethyl       Na    8          2-(methylthio)ethyl K    9          4-(BOC-amino)butyl  Na    10         aminocarbonylmethyl Li    11         N-BOC-imidazol-2-ylmethyl                                   Na    12         4-hydroxyphenyl     Na    13         hydrogen            Na    14         methyl              Na    15         4-fluorophenylmethyl                                   K    16         cyanomethyl         K    17         bromomethyl         Na    18         trifluoromethyl     Li    19         phenoxymethyl       K    20         phenylthiomethyl    Na    21         phenyl              Li    22         4-pyridyl           K    23         cyclohexyl          Na    24         cyclohexylmethyl    K    ______________________________________

                  TABLE 3    ______________________________________    3 #STR19##    Entry      R.sup.3             W    ______________________________________    1          isobutyl            Na    2          butyl               Na    3          sec-butyl           K    4          ethyl               Na    5          benzyl              Li    6          4-hydroxyphenylmethyl                                   Na    7          hydroxymethyl       Na    8          2-(methylthio)ethyl K    9          4-(BOC-amino)butyl  Na    10         aminocarbonylmethyl Li    11         N-BOC-imidazol-2-ylmethyl                                   Na    12         4-hydroxyphenyl     Na    13         hydrogen            Na    14         methyl              Na    15         4-fluorophenylmethyl                                   K    16         cyanomethyl         K    17         bromomethyl         Na    18         trifluoromethyl     Li    19         phenoxymethyl       K    20         phenylthiomethyl    Na    21         phenyl              Li    22         4-pyridyl           K    23         cyclohexyl          Na    24         cyclohexylmethyl    K    ______________________________________

                  TABLE 4    ______________________________________    4 #STR20##    Entry      R.sup.3             W    ______________________________________    1          isobutyl            Na    2          butyl               Na    3          sec-butyl           K    4          ethyl               Na    5          benzyl              Li    6          4-hydroxyphenylmethyl                                   Na    7          hydroxymethyl       Na    8          2-(methylthio)ethyl K    9          4-(BOC-amino)butyl  Na    10         aminocarbonylmethyl Li    11         N-BOC-imidazol-2-ylmethyl                                   Na    12         4-hydroxyphenyl     Na    13         hydrogen            Na    14         methyl              Na    15         4-fluorophenylmethyl                                   K    16         cyanomethyl         K    17         bromomethyl         Na    18         trifluoromethyl     Li    19         phenoxymethyl       K    20         phenylthiomethyl    Na    21         phenyl              Li    22         4-pyridyl           K    23         cyclohexyl          Na    24         cyclohexylmethyl    K    ______________________________________

                  TABLE 5    ______________________________________    5 #STR21##    Entry      R.sup.3             W    ______________________________________    1          isobutyl            Na    2          butyl               Na    3          sec-butyl           K    4          ethyl               Na    5          benzyl              Li    6          4-hydroxyphenylmethyl                                   Na    7          hydroxymethyl       Na    8          2-(methylthio)ethyl K    9          4-(BOC-amino)butyl  Na    10         aminocarbonylmethyl Li    11         N-BOC-imidazol-2-ylmethyl                                   Na    12         4-hydroxyphenyl     Na    13         hydrogen            Na    14         methyl              Na    15         4-fluorophenylmethyl                                   K    16         cyanomethyl         K    17         bromomethyl         Na    18         trifluoromethyl     Li    19         phenoxymethyl       K    20         phenylthiomethyl    Na    21         phenyl              Li    22         4-pyridyl           K    23         cyclohexyl          Na    24         cyclohexylmethyl    K    ______________________________________

                  TABLE 6    ______________________________________    6 #STR22##    Entry      R.sup.3             W    ______________________________________    1          isobutyl            Na    2          butyl               Na    3          sec-butyl           K    4          ethyl               Na    5          benzyl              Li    6          4-hydroxyphenylmethyl                                   Na    7          hydroxymethyl       Na    8          2-(methylthio)ethyl K    9          4-(BOC-amino)butyl  Na    10         aminocarbonylmethyl Li    11         N-BOC-imidazol-2-ylmethyl                                   Na    12         4-hydroxyphenyl     Na    13         hydrogen            Na    14         methyl              Na    15         4-fluorophenylmethyl                                   K    16         cyanomethyl         K    17         bromomethyl         Na    18         trifluoromethyl     Li    19         phenoxymethyl       K    20         phenylthiomethyl    Na    21         phenyl              Li    22         4-pyridyl           K    23         cyclohexyl          Na    24         cyclohexylmethyl    K    ______________________________________

                  TABLE 7    ______________________________________    7 #STR23##    Entry      R.sup.3             W    ______________________________________    1          isobutyl            Na    2          butyl               Na    3          sec-butyl           K    4          ethyl               Na    5          benzyl              Li    6          4-hydroxyphenylmethyl                                   Na    7          hydroxymethyl       Na    8          2-(methylthio)ethyl K    9          4-(BOC-amino)butyl  Na    10         aminocarbonylmethyl Li    11         N-BOC-imidazol-2-ylmethyl                                   Na    12         4-hydroxyphenyl     Na    13         hydrogen            Na    14         methyl              Na    15         4-fluorophenylmethyl                                   K    16         cyanomethyl         K    17         bromomethyl         Na    18         trifluoromethyl     Li    19         phenoxymethyl       K    20         phenylthiomethyl    Na    21         phenyl              Li    22         4-pyridyl           K    23         cyclohexyl          Na    24         cyclohexylmethyl    K    ______________________________________

                  TABLE 8    ______________________________________    1 #STR24##    Entry       R.sup.3             W    ______________________________________    1           isobutyl            Na    2           butyl               Na    3           sec-butyl           K    4           ethyl               Na    5           benzyl              Li    6           4-hydroxyphenylmethyl                                    Na    7           hydroxymethyl       Na    8           2-(methylthio)ethyl K    9           4-(BOC-amino)butyl  Na    10          aminocarbonylmethyl Li    11          N-BOC-imidazol-2-ylmethyl                                    Na    12          4-hydroxyphenyl     Na    13          hydrogen            Na    14          methyl              Na    15          4-fluorophenylmethyl                                    K    16          cyanomethyl         K    17          bromomethyl         Na    18          trifluoromethyl     Li    19          phenoxymethyl       K    20          phenylthiomethyl    Na    21          phenyl              Li    22          4-pyridyl           K    23          cyclohexyl          Na    24          cyclohexylmethyl    K    ______________________________________

                                      TABLE 9    __________________________________________________________________________    Entry    __________________________________________________________________________     ##STR25##                     3 #STR26##    4 #STR27##                     5 #STR28##     ##STR29##    6                 7 #STR30##                              8 #STR31##    9 #STR32##                 0 #STR33##                              1 #STR34##    2 #STR35##                 3 #STR36##                              4 #STR37##    __________________________________________________________________________

                  TABLE 10    ______________________________________    5 #STR38##    Entry   R.sup.1           R.sup.2    ______________________________________    1       methyl            benzyl    2       2-cyclohexenylmethyl                              2-cyclohexenylmethyl    3       2-propenyl        2-propenyl    4       benzoyl           hydrogen    5       2-pyridylmethoxycarbonyl                              hydrogen    6       trifluoroacetyl   hydrogen    7       diphenylmethyl    2-naphthylmethyl    8       isobutyl          isobutyl    9       ethyl             propenyl    10      2-cyclohexenylmethyl                              benzyl    11      acetyl            methyl    12      ethyl             ethyl    13      2-pyridylmethoxycarbonyl                              butyl    14      benzyl            cyclohexyl    15      4-methoxybenzyloxycarbonyl                              cyclopropyl    16      benzyloxycarbonyl phenyl    17      2-naphthylmethyl  4-methoxyphenyl    18      2-tetrahydrofuranoxycarbonyl                              hydrogen    19      2-thienylmethoxycarbonyl                              methyl    20                 R.sup.1 R.sup.2 N = pyrrolyl    21                 R.sup.1 R.sup.2 N = morpholinyl    22                 R.sup.1 R.sup.2 N = piperidinyl    23                 R.sup.1 R.sup.2 N = succinimido    ______________________________________

                  TABLE 11    ______________________________________    6 #STR39##    Entry   R.sup.1           R.sup.2    ______________________________________    1       methyl            benzyl    2       2-cyclohexenylmethyl                              2-cyclohexenylmethyl    3       2-propenyl        2-propenyl    4       benzoyl           hydrogen    5       2-pyridylmethoxycarbonyl                              hydrogen    6       trifluoroacetyl   hydrogen    7       diphenylmethyl    2-naphthylmethyl    8       isobutyl          isobutyl    9       ethyl             propenyl    10      2-cyclohexenylmethyl                              benzyl    11      acetyl            methyl    12      ethyl             ethyl    13      2-pyridylmethoxycarbonyl                              butyl    14      benzyl            cyclohexyl    15      4-methoxybenzyloxycarbonyl                              cyclopropyl    16      benzyloxycarbonyl phenyl    17      2-naphthylmethyl  4-methoxyphenyl    18      2-tetrahydrofuranoxycarbonyl                              hydrogen    19      2-thienylmethoxycarbonyl                              methyl    20                 R.sup.1 R.sup.2 N = pyrrolyl    21                 R.sup.1 R.sup.2 N = morpholinyl    22                 R.sup.1 R.sup.2 N = piperidinyl    23                 R.sup.1 R.sup.2 N = succinimido    ______________________________________

                  TABLE 12    ______________________________________    8 #STR40##    Entry   R.sup.1           R.sup.2    ______________________________________    1       methyl            benzyl    2       2-cyclohexenylmethyl                              2-cyclohexenylmethyl    3       2-propenyl        2-propenyl    4       benzoyl           hydrogen    5       2-pyridylmethoxycarbonyl                              hydrogen    6       trifluoroacetyl   hydrogen    7       diphenylmethyl    2-naphthylmethyl    8       isobutyl          isobutyl    9       ethyl             propenyl    10      2-cyclohexenylmethyl                              benzyl    11      acetyl            methyl    12      ethyl             ethyl    13      2-pyridylmethoxycarbonyl                              butyl    14      benzyl            cyclohexyl    15      4-methoxybenzyloxycarbonyl                              cyclopropyl    16      benzyloxycarbonyl phenyl    17      2-naphthylmethyl  4-methoxyphenyl    18      2-tetrahydrofuranoxycarbonyl                              hydrogen    19      2-thienylmethoxycarbonyl                              methyl    20      R.sup.1 R.sup.2 N = pyrrolyl    21      R.sup.1 R.sup.2 N = morpholinyl    22      R.sup.1 R.sup.2 N = piperidinyl    23      R.sup.1 R.sup.2 N = succinimido    ______________________________________

                  TABLE 13    ______________________________________    9 #STR41##    Entry   R.sup.1           R.sup.2    ______________________________________    1       methyl            benzyl    2       2-cyclohexenylmethyl                              2-cyclohexenylmethyl    3       2-propenyl        2-propenyl    4       benzoyl           hydrogen    5       2-pyridylmethoxycarbonyl                              hydrogen    6       trifluoroacetyl   hydrogen    7       diphenylmethyl    2-naphthylmethyl    8       isobutyl          isobutyl    9       ethyl             propenyl    10      2-cyclohexenylmethyl                              benzyl    11      acetyl            methyl    12      ethyl             ethyl    13      2-pyridylmethoxycarbonyl                              butyl    14      benzyl            cyclohexyl    15      4-methoxybenzyloxycarbonyl                              cyclopropyl    16      benzyloxycarbonyl phenyl    17      2-naphthylmethyl  4-methoxyphenyl    18      2-tetrahydrofuranoxycarbonyl                              hydrogen    19      2-thienylmethoxycarbonyl                              methyl    20      R.sup.1 R.sup.2 N = pyrrolyl    21      R.sup.1 R.sup.2 N = morpholinyl    22      R.sup.1 R.sup.2 N = piperidinyl    23      R.sup.1 R.sup.2 N = succinimido    ______________________________________

EXAMPLE 9 ##STR42## Determination of the stability of 2S-bis(phenylmethyl)amino!-3-phenylpropanal and 2S-bis(phenylmethyl)amino!-1-hydroxy-3-phenylpropylsulfonic acid, sodiumsalt

2S- bis(phenylmethyl)amino!-1-hydroxy-3-phenylpropylsulfonic acid,sodium salt was stored at ambient temperature in a capped, brown glassbottle ("Salt Sample") and periodically samples of the salt wasconverted into 2S- bis(phenylmethyl)amino!-3-phenylpropanal by themethod of Example 7. The experiment extended through 61 days with puritydeterminations made on days 0 (t=0), 3 (t=3), 6 (t=6), 18 (t=18) and 61(t=61). A sample of the salt was treated with aqueous potassiumcarbonate and extracted with ethyl acetate on day 0. The ethyl acetatewas removed under reduced pressure to provide the aldehyde and thissample was used as a t=0 (day 1) reference standard for the stabilitydetermination ("Aldehyde Sample"). The t=0 sample of the aldehyde wasthen stored at ambient temperature in a capped, brown glass bottle sideby side with the stored sample of the salt. The purity of the salt wasthen measured on days 3 (t=3), 8 (t=8), 15 (t=15) and 21 (t=21). Theidentity and purity of all samples was determined by HPLC by the methodof Example 7. The results of these studies are shown in Table 14.

                  TABLE 14    ______________________________________    Day     Aldehyde Sample                           Salt Sample    (t=)    (% aldehyde remaining)                           (% aldehyde remaining)    ______________________________________    0       99             99    3       94             99    6       --             100    8       64             --    15      23             --    18      10             --    21      --             99    61      --             99    ______________________________________

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims. From the foregoing description, one skilled in the artcan easily ascertain the essential characteristics of this invention,and without departing from the spirit and scope thereof, can makevarious changes and modifications of the invention to adapt it tovarious usages and conditions.

What is claimed is:
 1. Process of preparing a compound formula ##STR43##wherein R¹ represents alkyl, alkenyl, alkyl substituted with one or morearyl radicals, cycloalkenylalkyl, alkanoyl, haloalkanoyl, aroyl,alkoxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl or9-phenylfluoren-9-yl radicals;R² represents hydrogen, alkyl, alkenyl,aralkyl, cycloalkyl, cycloalkenylalkyl or aryl radicals; or --NR¹ R²represents heterocyclo or heteroaryl radicals; and R³ represents alkyl,haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl,alkylthioalkyl, arylthioalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,cycloalkyl or cycloalkylalkyl radicals; or R² and R³ together withnitrogen atom and the carbon atom to which they are bonded form aheterocyclo radical; wherein said process comprises treating a compoundrepresented by the formula ##STR44## wherein W represents a cation whichis capable of forming a sulfate salt; and R¹, R² and R³ are as definedabove, with an aqueous base solution.
 2. Process of claim 1 wherein Wrepresents a metal cation or a quaternary amine cation which is capableof forming a sulfate salt;R¹ represents alkyl of 1-8 carbon atoms,alkenyl of 2-8 carbon atoms, alkyl of 1-3 carbon atoms substituted with1-3 aryl radicals, alkyl of 1-3 carbon atoms substituted with acycloalkenyl radical of 3-8 ring members, alkanoyl of 1-4 alkyl carbonatoms, haloalkanoyl of 1-4 alkyl carbon atoms and 1-3 halo radicals,aroyl, alkoxycarbonyl of 1-8 alkyl carbon atoms, arylmethoxycarbonyl,heteroarylmethoxycarbonyl or 9-phenylfluoren-9-yl radicals; R²represents hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbonatoms, alkyl of 1-3 carbon atoms substituted with an aryl radical,cycloalkyl of 3-8 ring members, alkyl of 1-3 carbon atoms substitutedwith a cycloalkenyl radical of 3-8 ring members, or aryl radicals; or--NR¹ R² represents 5-6 ring membered heterocyclo, 5-6 ring memberedheteroaryl, benzo fused 5-6 ring membered heterocyclo or benzo fused 5-6ring membered heteroaryl radicals; and R³ represents alkyl radical of 1to 5 carbon atoms, haloalkyl radical of 1 to 5 carbon atoms, cyanoalkylradical of 1 to 5 alkyl carbon atoms, hydroxyalkyl radical of 1 to 5alkyl carbon atoms, alkoxyalkyl radical of 1 to 5 alkyl carbon atoms and1-3 alkoxy carbon atoms, aryloxyalkyl radical of 1 to 5 alkyl carbonatoms, alkylthioalkyl radical of 1 to 5 alkyl carbon atoms and 1-3alkylthio carbon atoms, arylthioalkyl radical of 1 to 5 alkyl carbonatoms, aryl radical, aralkyl radical of 1 to 5 alkyl carbon atoms,heteroaralkyl radical of 1 to 5 alkyl carbon atoms and 5-6 ring members,cycloalkyl radical of 3-8 ring members, or cycloalkylalkyl radical of 1to 5 alkyl carbon atoms and 3-8 ring members; or R² and R³ together withnitrogen atom and the carbon atom to which they are bonded form a 5-6ring membered heterocyclo radical or a benzo fused 5-6 ring memberedheterocyclo radical.
 3. Process of claim 2 wherein W represents a cationof lithium, sodium, potassium, calcium, manganese, magnesium, barium,chromium, iron, nickel, cobalt, copper, zinc, cadmium, tin or silver;R¹represents alkyl of 1-5 carbon atoms, alkenyl of 2-5 carbon atoms, alkylof 1-2 carbon atoms substituted with 1-3 aryl radicals, alkyl of 1-2carbon atoms substituted with a cycloalkenyl radical of 5-6 ringmembers, alkanoyl of 1-4 alkyl carbon atoms, haloalkanoyl of 1-2 alkylcarbon atoms and 1-3 halo radicals, aroyl, alkoxycarbonyl of 1-5 alkylcarbon atoms, arylmethoxycarbonyl, heteroarylmethoxycarbonyl or9-phenylfluoren-9-yl radicals; R² represents hydrogen, alkyl of 1-5carbon atoms, alkenyl of 2-5 carbon atoms, alkyl of 1-2 carbon atomssubstituted with an aryl radical, cycloalkyl of 3-6 ring members, alkylof 1-2 carbon atoms substituted with a cycloalkenyl radical of 5-6 ringmembers, or aryl radicals; or --NR¹ R² represents 5-6 ring memberedheterocyclo or benzo fused 5-6 ring membered heterocyclo radicals; andR³ represents alkyl radical of 1 to 5 carbon atoms, hydroxyalkyl radicalof 1 to 3 alkyl carbon atoms, methoxyalkyl radical of 1 to 3 alkylcarbon atoms, phenoxyalkyl radical of 1 to 3 alkyl carbon atoms,methylthioalkyl radical of 1 to 3 alkyl carbon atoms, arylthioalkylradical of 1 to 3 alkyl carbon atoms, aryl radical, aralkyl radical of 1to 3 alkyl carbon atoms, heteroaralkyl radical of 1 to 3 alkyl carbonatoms and 5-6 ring members, cycloalkyl radical of 5-6 ring members, orcycloalkylalkyl radical of 1 to 3 alkyl carbon atoms and 3-6 ringmembers; or R² and R³ together with nitrogen atom and the carbon atom towhich they are bonded form a 5-6 ring membered heterocyclo radicaloptionally substituted with hydroxy radical.
 4. Process of claim 3wherein W represents a cation of lithium, sodium, potassium, calcium,magnesium, barium, iron, nickel, copper or zinc;R¹ represents methyl,ethyl, ethenyl, propenyl, benzyl, diphenylmethyl, naphthylmethyl,trityl, cyclohexenylmethyl, acetyl, butyryl, chloroacetyl, fluoroacetyl,difluoroacetyl, trifluoroacetyl, benzoyl, 2-methylbenzoyl,2,6-dimethylbenzoyl, 2,4,6-trimethylbenzoyl, 2,4,6-triisopropylbenzoyl,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,phenylmethoxycarbonyl, (2-methylphenyl)methoxycarbonyl,(4-methylphenyl)methoxycarbonyl, (4-methoxyphenyl)methoxycarbonyl,pyridylmethoxycarbonyl, or 9-phenylfluoren-9-yl radicals; R² representshydrogen, methyl, ethyl, ethenyl, propenyl, cyclohexenylmethyl, benzylor naphthylmethyl radicals; or --NR¹ R² represents pyrrolidinyl,piperidinyl, pyrrolyl, 2-isoindolinyl, phthalimidyl, succinimidyl ormaleimidyl radicals; and R³ represents methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, hydroxymethyl, hydroxyethyl,methoxyethyl, phenoxymethyl, methylthioethyl, phenylthiomethyl,phenylthioethyl, naphthylthiomethyl, naphthylthioethyl, phenyl,naphthyl, benzyl, 4-fluorobenzyl, 4-methylbenzyl, 4-methoxybenzyl,naphthylmethyl, imidazolylmethyl, cyclohexyl or cyclohexylmethylradicals; or R² and R³ together with nitrogen atom and the carbon atomto which they are bonded form pyrrolidinyl, 3-hydroxypyrrolidinyl,4-hydroxypyrrolidinyl, piperidinyl, 3-hydroxypiperidinyl,4-hydroxypiperidinyl or 5-hydroxypiperidinyl radicals.
 5. Process ofclaim 4 wherein W represents a cation of lithium, sodium or potassium;R¹represents methyl, ethyl, benzyl, diphenylmethyl, naphthylmethyl,trityl, trifluoroacetyl, tert-butoxycarbonyl, phenylmethoxycarbonyl or(4-methoxyphenyl) methoxycarbonyl radicals; R² represents hydrogen,methyl, ethyl or benzyl radicals; or --NR¹ R² represents 2-isoindolinyl,phthalimidyl, succinimidyl or maleimidyl radicals; and R³ representsmethyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,methylthioethyl, phenylthiomethyl, naphthylthiomethyl, benzyl,4-fluorobenzyl, 4-methylbenzyl, 4-methoxybenzyl, naphthylmethyl,imidazolylmethyl or cyclohexylmethyl radicals; or R² and R³ togetherwith nitrogen atom and the carbon atom to which they are bonded formpyrrolidinyl or piperidinyl radicals.
 6. Process of claim 5 wherein 2S-bis(phenylmethyl) amino!-3-phenylpropanal is prepared from 2S-bis(phenylmethyl)amino!-1-hydroxy-3-phenylpropylsulfonic acid, sodiumsalt.
 7. Process of claim 1 wherein said aqueous base solution isaqueous sodium carbonate, potassium carbonate, sodium hydroxide,potassium hydroxide, ammonium hydroxide, magnesium oxide or calciumoxide.
 8. Process of claim 1 wherein said aqueous base solution furthercomprises an equilibrium exchange agent.